Factors contributing to the improvement in J-HAQ after 3 years of treatment with abatacept in biologic-naïve rheumatoid arthritis patients: Interim results of a long-term, observational, multicentre study in Japan (ORIGAMI).

OBJECTIVES: We investigated the long-term effectiveness, safety, and factors affecting Japanese Health Assessment Questionnaire (J-HAQ) improvement during abatacept treatment in Japanese rheumatoid arthritis (RA) patients. METHODS: The ORIGAMI study is an ongoing observational study of biologic-naïve RA patients with moderate disease activity treated with subcutaneous abatacept (125 mg, once-weekly). Patients treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) were extracted from the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) registry as an historical, weighted control group. The primary endpoint for this interim analysis was the proportion of patients with J-HAQ remission (score ≤0.5) at 3 years. RESULTS: Among 279 abatacept-treated and 220 csDMARD-treated patients, J-HAQ remission was achieved at 3 years in 40.5% (95% confidence interval [CI] 34.7%-46.2%) and 28.9% (95% CI 9.9%-47.8%), respectively. Age, RA duration <1 year, baseline J-HAQ score, and Simplified Disease Activity Index remission at 6 months were associated with 3-year J-HAQ remission in the abatacept group. Overall, 24/298 patients (8.1%; safety analysis set) experienced serious adverse drug reactions with an incidence of 5.3 per 100 person-years. CONCLUSIONS: This study confirmed the 3-year effectiveness and safety, and revealed potential factors associated with J-HAQ remission in biologic-naïve RA patients treated with abatacept in real-world clinical practice.

Associations of disease duration and anti-citrullinated peptide antibody status with the effectiveness of abatacept in biologic-naïve patients with rheumatoid arthritis: Post hoc analysis of a multicentre, real-world observational study in Japan (ORIGAMI).

OBJECTIVES: The aim of the article is to investigate the associations of disease duration and anti-cyclic citrullinated peptide antibody (ACPA) status with the effectiveness of abatacept in biologic-naïve patients with rheumatoid arthritis (RA). METHODS: We performed post hoc analyses of the Orencia® Registry in Geographically Assembled Multicenter Investigation (ORIGAMI) study of biologic-naïve RA patients aged ≥20 years with moderate disease activity who were prescribed abatacept. Changes in the Simplified Disease Activity Index (SDAI) and Japanese Health Assessment Questionnaire (J-HAQ) at 4, 24, and 52 weeks of treatment were analysed in patients divided according to ACPA serostatus (positive/negative), disease duration (<1/≥1 year), or both. RESULTS: SDAI scores decreased from baseline in all groups. SDAI scores tended to decrease more in the ACPA-positive group and disease duration <1-year group than in the ACPA-negative group and disease duration ≥1-year group, respectively. In the disease duration <1-year group, SDAI tended to decrease more in the ACPA-positive group than in the ACPA-negative group. Disease duration was independently associated with the change in SDAI and SDAI remission at Week 52 in multivariable regression models. CONCLUSIONS: These results suggest that starting abatacept within 1 year of diagnosis was associated with greater effectiveness of abatacept in biologic-naïve patients with RA and moderate disease activity.

Effectiveness and safety of subcutaneous abatacept in biologic-naïve RA patients at Week 52: A Japanese multicentre investigational study (ORIGAMI study).

OBJECTIVES: To evaluate the effectiveness and safety of abatacept over 52 weeks in biologic-naïve rheumatoid arthritis (RA) patients with moderate disease activity in the prospective, 5-year, observational study (ORIGAMI study) in Japan. METHODS: Abatacept (125 mg) was administered subcutaneously once a week. Clinical outcomes included Simplified Disease Activity Index (SDAI) remission at Week 52 (primary endpoint), Japanese Health Assessment Questionnaire (J-HAQ), EuroQol 5-Dimension Questionnaire (EQ-5D), treatment retention, and safety. The results were compared with those of conventional synthetic disease-modifying antirheumatic drug (csDMARD) controls from the ongoing Institute of Rheumatology, Rheumatoid Arthritis (IORRA) registry. RESULTS: Overall, 325 patients were enrolled, with a mean age of 66.9 ± 12.7 years. The proportion of patients achieving SDAI remission (≤3.3) at Week 52 was 18.9% (95% CI: 14.3-23.6) and low disease activity (≤11) was 53.3% (95% CI: 47.4-59.1). A significant improvement was observed in J-HAQ and EQ-5D over 52 weeks in both the abatacept and csDMARD groups. The probability of abatacept treatment retention at Week 52 was 69.9% (95% CI: 64.7-75.5). Adverse events and serious adverse events were reported in 50.0% and 12.1% of patients, respectively. CONCLUSIONS: Abatacept significantly improved disease activity, physical disability, and quality of life for up to 52 weeks in RA patients in a real-world setting.

Effects of Polymethoxyflavonoids on Bone Loss Induced by Estrogen Deficiency and by LPS-Dependent Inflammation in Mice.

Polymethoxyflavonoids (PMFs) are a family of the natural compounds that mainly compise nobiletin, tangeretin, heptamethoxyflavone (HMF), and tetramethoxyflavone (TMF) in citrus fruits. PMFs have shown various biological functions, including anti-oxidative effects. We previously showed that nobiletin, tangeretin, and HMF all inhibited interleukin (IL)-1-mediated osteoclast differentiation via the inhibition of prostaglandin E2 synthesis. In this study, we created an original mixture of PMFs (nobiletin, tangeretin, HMF, and TMF) and examined whether or not PMFs exhibit co-operative inhibitory effects on osteoclastogenesis and bone resorption. In a coculture of bone marrow cells and osteoblasts, PMFs dose-dependently inhibited IL-1-induced osteoclast differentiation and bone resorption. The optimum concentration of PMFs was lower than that of nobiletin alone in the suppression of osteoclast differentiation, suggesting that the potency of PMFs was stronger than that of nobiletin in vitro. The oral administration of PMFs recovered the femoral bone loss induced by estrogen deficiency in ovariectomized mice. We further tested the effects of PMFs on lipopolysaccharide-induced bone resorption in mouse alveolar bone. In an ex vivo experimental model for periodontitis, PMFs significantly suppressed the bone-resorbing activity in organ cultures of mouse alveolar bone. These results indicate that a mixture of purified nobiletin, tangeretin, HMF, and TMF exhibits a co-operative inhibitory effect for the protection against bone loss in a mouse model of bone disease, suggesting that PMFs may be potential candidates for the prevention of bone resorption diseases, such as osteoporosis and periodontitis.

Does recyclable separation reduce the cost of municipal waste management in Japan?

Municipal solid waste (MSW) management is a system involving multiple sub-systems that typically require demanding inputs, materials and resources to properly process generated waste throughput. For this reason, MSW management is generally one of the most expensive services provided by municipalities. In this paper, we analyze the Japanese MSW management system and estimate the cost elasticity with respect to the waste volumes at three treatment stages: collection, processing, and disposal. Although we observe economies of scale at all three stages, the collection cost is less elastic than the disposal cost. We also examine whether source separation at home affects the cost of MSW management. The empirical results show that the separate collection of the recyclable fraction leads to reduced processing costs at intermediate treatment facilities, but does not change the overall waste management cost. Our analysis also reveals that the cost of waste management systems decreases when the service is provided by private companies through a public tender. The cost decreases even more when the service is performed under the coordination of adjacent municipalities.

Use of a novel orbicularis oculi muscle overlap method for correction of tear-trough deformity.

BACKGROUND: Although the fat-pad-sliding method reported by Loeb and the "arcus marginalis release with preservation of orbital fat" method reported by Hamra are useful techniques for correcting tear trough deformity in the Asian population, including Japanese patients, occasional cases of tear-trough deformity have persisted even after surgery. To solve this problem, the authors developed a novel orbicularis oculi muscle overlap method, which has enabled them to obtain good results. METHODS: The orbicularis oculi muscle overlap method was performed for 10 patients (9 women and 1 man) with prominent tear-trough deformity. The average of these patients was 52 years (range, 34-72 years). The origin of the orbicularis oculi muscle was elevated at its adherence to the maxillary bone, and the innermost portion of the origin of the orbicularis oculi muscle was excised by a width of 6 to 7 mm to reduce the muscle tension. This muscle flap was overlapped relative to the orbital fat, which was repositioned over the orbital rim and sutured in place. RESULTS: Tear-trough deformity improved in all cases, and the patients were highly satisfied with their flat lower eyelids. CONCLUSION: The orbicularis oculi muscle overlap method is effective for thin eyelids with prominent tear-trough deformity. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

The Effect of Control-released Basic Fibroblast Growth Factor in Wound Healing: Histological Analyses and Clinical Application.

BACKGROUND: Basic fibroblast growth factors (bFGFs) play a crucial role in wound healing by promoting fibroblast proliferation and neovascularization. However, drawback of bFGF is short half-life in free form. Gelatin has a capability of sustaining growth factors, which are gradually released while degradation. The purpose of this study is to see whether bFGF-impregnated gelatin sheet is effective in a murine model and whether it could also be available for patients in a safe manner. METHODS: Full-thickness skin defect was created on C57BL/6J mice and covered with bFGF with gelatin sheet (group A), bFGF without gelatin sheet (group B), phosphate buffer saline (PBS) with gelatin sheet (group C), and only PBS (group D). Wound healing was evaluated in terms of percent wound closure, granulation thickness, wound maturity, and vascular density. Clinical trial was conducted for patients who received either acute or chronic ulcers. The sheets were put onto the wounds and covered by hydrocolloid dressing, which was changed weekly. RESULTS: Groups A and B exhibited better wound healing than groups C and D in all aspects. Moreover, group A showed better results than group B at day 7 in terms of wound closure, collagen maturity, and vascularity. Efficacy without any adverse events was found in the clinical series. CONCLUSIONS: These findings suggest that control-released bFGF using gelatin sheet is effective for promoting wound healing. Such therapeutic strategy was considered to offer several clinical advantages including rapid healing and reduction of the dressing change with less patient discomfort.

Elastase inhibition reduced death associated with acid aspiration-induced lung injury in hamsters.

This study examined whether the specific inhibition of neutrophil elastase by sivelestat sodium hydrate (sivelestat) reduced deaths associated with severe acute lung injury after hydrochloric acid (HCl) aspiration in hamsters. Animals that received a single intratracheal instillation of HCl (0.2 N, 200 microL) time-dependently died by occlusion of their trachea with inflammatory exudate. In a time course study, these animals developed severe lung injury, peaking 12 to 24 h after HCl instillation, as indicated by hemorrhage and a massive increase in the protein concentration of bronchoalveolar lavage fluid. These changes were closely correlated with neutrophil elastase activity in bronchoalveolar lavage fluid. Sivelestat (0.01, 0.1 and 1 mg/kg/h), when intravenously infused during the first 48 h post-HCl instillation, dose-dependently reduced death in HCl-instilled hamsters. In a separate experiment, analysis of bronchoalveolar lavage fluid parameters and partial pressure of arterial oxygen (PaO(2)) 8 h post-HCl instillation showed that sivelestat at 1 mg/kg/h, i.v. significantly improved both bronchoalveolar lavage fluid parameters and PaO(2) levels with evidence of the inhibition of neutrophil elastase activity in bronchoalveolar lavage fluid. These results suggest that neutrophil elastase plays a significant role in this type of severe acute lung injury that leads to death by respiratory failure.